As used herein, "annealing" refers to a process of subjecting the liquid dispersion or article formed therefrom to a specified, elevated temperature for a predetermined minimum period of time and then allowing the dispersion or article to cool to ambient conditions.
Transdermal delivery devices comprising a dispersion of a drug or other biological agent in various aqueous or non-aqueous matrices are known in the art as described in U.S. Pat. Nos. 3,598,122, 3,598,123, 4,031,894, 4,144,317, 4,201,211, 4,262,003, 4,379,454, and 4,436,741, all of which are incorporated herein in their entirety by reference. As disclosed in these patents, aqueous matrices typically comprise water or water/ethanol and 1-5 wt. % of a gelling agent such as hydroxyethylcellulose. Non-aqueous matrices are typically comprised of a polymeric material such as copolymers of ethylene vinyl acetate or blends of low molecular weight and high molecular weight polyisobutene. The drug may be in solid form or in the form of a liquid dispersion. This invention relates to such liquid drug dispersions.
In addition to the above mentioned patents, U.S. Pat. No. 5,370,924, incorporated herein in its entirety by reference, discloses methods for manufacturing transdermal drug delivery devices. The methods disclosed in this patent describe a process whereby the various elements of a transdermal device may be fabricated separately and joined together in a final manufacturing step.
Although this invention will be described hereafter specifically with respect to scopolamine delivery devices, it should be recognized that it is applicable to dispersions of any other drug or biological agent in matrices where a crystalline structure may be formed. Such drugs or agents such as nicotine, secoverine, and benztropine, for example, may, to the extent they form crystalline structures, be treated in a manner similar to the methods by which dispersions of scopolamine base are treated according to this invention.
Transdermal delivery devices for the administration of scopolamine of the type disclosed in U.S. Pat. No. 4,031,894 cited above are used extensively for the prevention of motion sickness. The original manufacture of the product is described in the patent by solvent casting of chloroform solutions of scopolamine base in polyisobutene (PIB) and mineral oil (MO) onto impermeable webs to form drug reservoir and contact adhesive films. Upon evaporation of the chloroform, a dispersion of liquid scopolamine base in the PIB/MO matrix is formed. The drug reservoir and contact adhesive films are then laminated to opposite sides of a release rate controlling membrane, formed from a mineral oil impregnated microporous film, to produce a final laminate comprising a removable release liner layer, an adhesive layer, a rate controlling membrane layer, a drug reservoir layer, and an impermeable backing lamina. The final laminate is then die cut into individual systems and packaged in individual heat sealed pouches.
The manufacture of the product in this manner was carried out for approximately five years without any indication of the formation of crystals in either the drug reservoir or the adhesive. After that time, small crystals of scopolamine hydrate were observed infrequently but this did not present a problem because the release rate of the drug from the device was not affected by the presence of the small number of small crystals then occurring. In addition to the small number and size of the crystals, another reason that the release rates were not affected is attributed to the observation that the crystal size did not change appreciably (i.e. minimal if any crystal growth) with time in the pouch.
Approximately two years later, larger numbers of rapidly propagating crystals were observed in the drug reservoir, with a lower incidence observed in the contact adhesive layer which contained a lower concentration of scopolamine base. At that time, the size of the crystals and their frequency of occurrence had increased to the point where they produced a significant adverse effect on the release rate of scopolamine from the device. Thereafter, every lot manufactured developed unacceptably high crystal size and frequency and commercial production had to be halted until the problem could be solved.
Crystallization was most noticeable after the step in which the final laminate film was cut into individual devices. After the final laminate film was fed through the die-cutting machine for the formation of individual transdermal delivery units, crystallization began around the edges of the cut product and crystalline growth thereafter propagated rapidly throughout the mass of the reservoir and in some cases the adhesive layer. Visually observable crystals were not necessarily apparent immediately after the cutting step; instead they would typically develop over a period of days. These crystals were identified as a hydrate form of scopolamine base.
Various attempts to eliminate the problem were tried over the next several months, all to no avail. For example, the drug reservoir film, adhesive film, and the final laminate film were heated overnight, yet crystallization after die-cutting still occurred. Similarly, the casting solutions were heated and allowed to stand for extended periods also with no effect. Attempts to reduce the amount of residual water in the chloroform solution of the scopolamine base by drying with extra amounts of drying agents such as anhydrous sodium sulfate and magnesium sulfate were also unsuccessful as crystallization still occurred. Extensive cleaning of contacting surfaces reduced but did not eliminate the presence of crystals after die-cutting.
A successful process for the prevention of the formation of the scopolamine hydrate crystals was ultimately discovered and is described in U.S. Pat. No. 4,832,953, incorporated in its entirety herein by reference. According to that invention, formation of crystalline hydrates in a liquid dispersion of a hydratable liquid in a non-aqueous, typically polymeric, matrix can be prevented if, after they have been placed in their packages, the articles are heated to a temperature above the melting point of the crystalline hydrate, are maintained at that temperature for a period of time, and then are allowed to cool to ambient conditions. For this process to be successful, holding times for cast films and laminates, prior to die-cutting, pouching, and annealing, were minimized in an effort to outrace the kinetics of crystal growth. It was found that when so treated, crystals initially present disappeared, did not reform upon cooling to ambient conditions, and there were no additional signs of crystal formation or growth after storage at ambient conditions and under accelerated aging conditions for several months.
The commercial manufacture of the product including the step of annealing the pouched systems as described in U.S. Pat. No. 4,832,953 was then carried out for approximately seven years before the current crystallization problem developed and commercial production again had to be halted. The measures employed to prevent formation of the hydrate as taught in the 4,832,953 patent are not effective in preventing the formation of the newly observed crystals because: 1) the new crystals do not melt at the annealing temperatures specified therein; and 2) the kinetics of the new crystal growth are significantly faster, such that films cannot practically be moved through the manufacturing process fast enough to eliminate significant crystal growth. Crystals have been observed only four hours after film casting and have been observed in the final product.
An extensive investigation was undertaken, including examination of raw materials, process equipment, and procedures to isolate a source of crystallization, during which it was determined that crystal formation could not be attributed to any specific feature of the procedures, equipment, or raw materials used to produce the product. It was confirmed that rapid crystallization could start after any manufacturing step involving the scopolamine films and laminates. Production was halted until the problem was solved according to this invention.